Animal Science Department

 

Date of this Version

5-2011

Comments

A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements
For the Degree of Master of Science, Major: Animal Science
Under the Supervision of Professor Jennifer R. Wood
Lincoln, Nebraska: May, 2011

Copyright 2011 Zhufeng Yang

Abstract

Individuals who are overweight or obese are at increased risk for cancer. However, the mechanistic link between obesity and cancer is poorly defined. Adipose tissue produces hormones and pro-inflammatory cytokines with mitogenic properties. Many of these hormones and cytokines are altered in obese individuals and may lead to disruption of the normal balance between cell proliferation, differentiation, and apoptosis. Thus, the objective of this study was to determine how adipocyte-derived factors regulate the expression of genes that contribute to cell proliferation and migration. To compare immediate early gene (cell proliferation) and epithelial-mesenchymal transition (cell migration) gene expression between untreated and treated cells, HeLa cells were exposed to IGF-1 (100ng/ml), leptin (100ng/ml), TNFa (10ng/ml), or IL-6 (10ng/ml) and QPCR analyses were carried out. Immediate early gene expression was regulated by all four hormones. Specifically, IGF-1 increased Jun, Fos, and Il-8; leptin increased Jun and Il-6; IL-6 increased Fos, Il-6, and Il-8; and TNFa increased Jun, Fos, Il-6, and Il-8 mRNA abundance. Genes that regulate the epithelial-mesenchymal transition were also regulated by IGF-1, IL-6, and TNF. Specifically, IGF-1 increased Snail1 and Snail2; IL-6 increased Snail1; and TNF increased Jag1 mRNAs. Interestingly, the expression of Snail1, Snail2, JUN, and FOS was increased in the uterus of age-matched obese compared to normal-weight mice. Western blot analyses demonstrated that these changes in mRNA abundance were associated with increased phosphorylation of Akt, Erk1/2, Jnk, and Stat3 in treated compared to untreated cells suggesting that these signaling factors play a role in the regulation of immediate early and epithelial-mesenchymal transition gene expression. These studies demonstrate for the first time a mechanistic link between factors produced and secreted by adipocytes and the expression of genes associated with cell transformation, proliferation, and migration. These cell functions play an important role in tumorigenesis and therefore changes in their expression may provide a plausible mechanism for obesity-dependent increases in a myriad of cancers

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